Some of the drugs that interact with DNA are among our most useful drugs in the treatment of neoplastic diseases. The agents and many derivatives bind to DNA and produce strand scission. We developed a model to evaluate parameters of their actions and now use the model to study drug metabolism and activation in tumors and in tissues that are selectively intoxicated. Studies are carried out with tumor cells and membranes and animal mitochondria, microsomes, and enzymes to define the systems of activation and to evaluate the means for control of their toxicity. Studies with phospholipids and enzymes indicate biotransformation of the agents to forms that may be proximal to the final reactants which bind covalently to macromolecules. Pharmacokinetic studies in progress are aimed to relate in vitro drug metabolism and drug activation to biological activity of the agents.